Angiogenesis is a process of forming new capillaries as endothelial cells of pre-existing blood vessels decompose, extracellular matrix, migrate, divide, and differentiate to form forming new capillaries, which may occur during a physiological process, such as growth, reproduction, or healing wounds. Also, angiogenesis is related to pathological states, such as tumor growth, arthritis, diabetes. Angiogenesis requires a complicated series of processes including growth, migration, and differentiation of vascular endothelial cells, capillary formation, or the like, and many angiogenesis promoting factors and angiogenesis suppressing factors in the process have been discovered. The angiogenesis suppressing factors are activated to counteract the angiogenesis promoting factors. Since toxicity of angiogenesis suppressants naturally present in a body is low, the angiogenesis suppressants may be used to suppress pathological angiogenesis, and thus many medications related to the angiogenesis suppressants are under development.
Excessive formation of blood vessels may become a main cause of worsening a disease, but non-formation of blood vessels also causes a serious disease. Angiogenesis is a necessary phenomenon for healing wounds or regenerating tissue, and thus, for example, a placenta with undeveloped angiogenesis becomes an important cause of miscarriage, and necrosis, ulceration, and ischemia due to the non-formation of blood vessels may cause dysfunction of the tissue or organ, or may cause death. Moreover, unsmooth flow of blood is a cause of diseases, such as arteriosclerosis, myocardial infarction, and angina. Thus, a treatment needs to be developed so that tissue damage caused by a low-oxygen state or low-nutrient state due to the non-formation of blood vessels may be reduced, and angiogenesis may be induced or promoted for smooth tissue regeneration.
Particularly, angiogenesis must be accompanied by a wound healing process necessary for regenerating wounded skin tissue. At a beginning stage of the wound, an inflammatory reaction caused by necrosis of cells and rupture of blood vessels occurs, and a series of processes of forming a biological medium material, such as callicrein, thrombin, or plasmin, may be followed after the inflammatory reaction along with a phenomenon of leaking out blood components, activation of platelets, and blood coagulation.
A treatment of physiological diseases using angiogenesis is referred to as an angiogenesis treatment, which is known as being effective in treating an angiogenesis-dependent ailment selected from the group consisting of a wound, chronic ulcer, ischemic stroke, myocardial infarction, angina pectoris, and cerebrovascular dementia. (KR 2009-0010662).
An angiogenesis promoting factor such as a vascular endothelial growth factor (VEGF) is already used as a medication for severe anemia. Also, angiogenesis promoting factors, such as a fibroblast growth factor, an epidermal growth factor, a platelet-derived epidermal growth factor, or the like, have been studied for clinical treatments. However, the factors are proteins that are difficult to be separated or purified and are expensive and thus are difficult to be clinically applied.
VEGF is a typical protein controlling angiogenesis. VEGF combines with a VEGF receptor 1, 2, or 3 (VEGFR1, VEGFR2, or VEGFR3) present in vascular endothelial cells, induces phosphorylation of tyrosine present in the VEGF receptor, and brings about activation of the vascular endothelial cells, thus consequently VEGF has a profound effect on the process of angiogenesis. Phosphorylation in VEGFR2 serves as the most important receptor in an angiogenesis signal transduction mechanism. Among medications using VEGF as a target, the most typical medication that is clinically used is Avastin, which corresponds to a VEGF neutralizing antibody and is approved by the FDA.
Heat shock protein (HSP) 27, which is a protein with a low molecular weight and has a charperon activity, self-aggregates to form clusters with respect to external environment factors, such as free radicals, heat, toxins, or the like, and thus has a defense ability to the external environment factors (NCBI Gene Bank Accession Number: NP—001531.1). Secretion of HSP 27 with a low molecular weight (HSP27 is produced in a human, and HSP25 is produced in a rat) has been confirmed by the present inventors. Many functions of HSP27 are known; for example, the HSP27 combines with a protein inducing apoptosis of cancer cells and increases resistance of cancer cells to radiation and anticancer drugs (Oncogene. May 26, 2005; 24(23):3715-25). However, relationships of HSP27 with VEGF, angiogenesis promotion, or wound healing promotion are not known.